This is an exploratory proposal aimed at characterizing the microenvironment of bone tissue around osteocyte lacunae (herein referred to as peri-lacunar tissue) as a function of age. Comprising nearly 90% of all bone cells, osteocytes are ideally situated to sense mechanical strain (or a lack of strain) and translate mechanical signals into biochemical signals to regulate bone modeling and remodeling. We have shown that there is an amplification of globally applied macroscopic bone strains at the microstructural level of the osteocyte due to the strain concentrating effect of the osteocyte lacuna and surrounding extracellular matrix. Our preliminary data indicates that the peri-lacunar bone tissue can have different material and mechanical properties than bone tissue not associated with an osteocyte lacuna and that these alterations can result in significant changes in prei-lacunar tissue strain. Our global hypothesis is that the aging extracellular matrix (ECM) attenuates the strain signals sensed by osteocytes. Specifically, we hypothesize that the local peri-lacunar strain decreases as a function of increasing age at given macroscopic, whole bone strain levels and that this decrease in peri-lacunar tissue strain is a result of age-related increases in mineral-to-collagen ratio and declines in collagen integrity in the peri-lacunar tissue. To test this hypothesis, we propose to examine if ultrastructural properties near the lacunae change with age and if such changes are associated with a decrease in strain concentration around lacunae. We propose the following specific aims: Specific Aim 1: We will measure osteocyte peri-lacunar tissue deformation in human cortical bone from donors of varying age. We hypothesize that for the same macroscopic bone strain, the local peri-lacunar tissue strain will decrease as a function of donor age. Specific Aim 2: We will characterize the material properties of the extracellular matrix surrounding osteocytes in cortical bone from donors of varying age. We hypothesize that the mineral-to-collagen ratio, stiffness, and stable cross-links will be higher in older bone than in younger bone. The findings from the proposed research project will offer new insights in bone mechanotransduction and a better understanding of age-related declines in bone strength. This new understanding may lead to improved treatment for bone diseases such as osteoporosis. [unreadable] [unreadable] [unreadable]